ASCO 2025: Highlights from Day 3

TROPION-Lung02: Efficacy of Datopotamab Deruxtecan (Dato-DXd) plus Pembrolizumab (Pembro) with or without Platinum Chemotherapy in First-Line aNSCLC Therapy

• The confirmed objective response rates were 55% for the doublet (Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone) and 56% for the triplet, with DCRof 88% and 89%, respectively
• mDoR was 20.1 mo (doublet) and 13.7 mo(triplet)
• mPFSwas reported as 11.2 mo (doublet), with 6.8 mo for the triplet group
• Common AE’s included stomatitis (57% in the doublet group and 33% in the triplet group) and nausea (42% doublet, 48% triplet), mainly Grade 1–2, with serious treatment-related AEs reported in 12% of doublet patients and 22% of triplet patients

Reference

Benjamin Levy et al, TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC). JCO 43, 8501, (2025).       

Phase 2b REZILIENT1 Study: Zipalertinib in Patients with Advanced EGFR Exon 20 Insertion Mutant NSCLC Post-Platinum Chemo with or without Amivantamab

• Zipalertinib achieved a confirmed objective response rate (cORR) of 35.2%, with a mDoR of 8.8 mo and a mPFS of 9.5 mo.
• In patients treated with platinum-based chemotherapy without prior amivantamab, the cORR was 40.0%. Among the 51 patients with prior amivantamab, those without other exon 20 insertion-directed therapies had a cORR of 30.0%, while those who received additional treatments had a cORR of 14.3%.
• In patients with brain metastases, the systemic cORR was 30.9%.
• The most common treatment-emergent adverse events (TEAEs) included paronychia, rash, anemia, and diarrhea, primarily grade 1 or 2, indicating a manageable safety profile for zipalertinib in this patient population.

Reference

Helena Yu et al, Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. JCO 43, 8503, (2025).

HERTHENA-Lung02 Study: Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated Advanced NSCLC Post-Third-Generation EGFR TKI

• HER3-DXd showed a significant improvement in PFScompared to platinum-based chemotherapy (PBC), with median PFS of 5.8 mo vs 5.4 mo (HR 0.77; P=0.011).
• The ORR was 35.2% for HER3-DXd versus 25.3% for PBC, with mDoR of 5.7 mon vs 5.4 mo, respectively.
• Treatment-emergent adverse events (TEAEs) occurred in nearly all patients; grade ≥3 TEAEs were more common with HER3-DXd (73%) than PBC (57%), primarily due to higher thrombocytopenia rates.

Reference

Tony Mok et al, Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study. JCO 43, 8506, (2025).

OptiTROP-Lung03 Study: Sacituzumab Tirumotecan (sac-TMT) in Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer

• In a study of 137 patients with advanced EGFRm NSCLC, those receiving sac-TMT (n=91) showed a higher treatment continuation rate (25.3%) compared to docetaxel (4.3%) at a median follow-up of 12.2 mo.
• Sac-TMT demonstrated superior clinical outcomes: confirmed overall response rate (ORR) was 45.1% vs 15.6% for docetaxel (p=0.0004), and median PFS was 6.9 mo vs 2.8 mo (HR 0.30, p<0.0001).
• OS was not reached for sac-TMT; the adjusted median OS for docetaxel was 9.3 mo (HR 0.36, p=0.007).
• Grade ≥3 treatment-related adverse events occurred in 56.0% of sac-TMT patients vs 71.7% with docetaxel, indicating a more manageable safety profile for sac-TMT.

Reference

Li Zhang et al, Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated non-small cell lung cancer (NSCLC): Results from the randomized OptiTROP-Lung03 study. JCO 43, 8507, (2025).

ABCSG 45 Phase II Trial: Neo-adjuvant Olaparib/Carboplatin (OC) vs Docetaxel/Epirubicin/Cyclophosphamide (TAC) in Patients with Early TNBC with Homologous Recombination Deficiency (HRD)

• Six cycles of TAC resulted in significantly high rates of RCB0/1 and pCR as compared to OC, 70.5% vs 52.2% and 59.1% vs 47.8% respectively, regardless of the BRCA1/2 status
• Higher rate of pCR was achieved with OC in BRCA1/2 PV; 77.3% vs 65%, however, it was less effective in BRCA1/2 WT
• Incidence of grade >3 hematologic toxicities was higher with OC treatment; 30% vs 3% thrombocytopenia and 43% vs 18% neutropenia

Reference

Christian Singer et al, Prospective randomized phase II trial to assess the efficacy and safety of neo-adjuvant olaparib/carboplatin (OC) in comparison to docetaxel/epirubicin/cyclophosphamide (TAC) in patients with early triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD): Primary results from the ABCSG 45 trial. JCO 43, 510, (2025). 

Alliance A092104 Phase 2/3 Study in Advanced Uterine Leiomyosarcoma After Progression on Prior Chemotherapy: Olaparib Plus Temozolomide vs Investigator’s Choice

• Survival outcomes were poor with T+O; median PFS 3.2 vs 5.6 mo
• Median PFS was 5.6 and 3.8 months with Tb and P respectively
• Rate of hematologic AEs was higher with olaparib plus temozolomide (T+O) vs investigator’s choice of trabectedin (Tb) or pazopanib (P)Results indicate the need for a marker to further assess the safety and efficacy of PARP inhibitor-based regimens in advanced uterine leiomyosarcoma

Reference

Brian Van Tine et al, Alliance A092104: A randomized phase 2/3 study of olaparib plus temozolomide versus investigator’s choice for the treatment of patients with advanced uterine leiomyosarcoma after progression on prior chemotherapy. JCO 43, 11507, (2025). 

Long-term results of KEYNOTE-412 Trial: Pembrolizumab (pembro) or Placebo (pbo) plus Concurrent Chemoradiotherapy (CRT) for Unresected, Locally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

• Pembro+CRT demonstrated superior event-free survival (EFS) vs pbo+CRT at the end of trial with >2 years of additional follow-up
• EFS was longer with pembro + CRT (HR:0.79) with 46.3% and 54% EFS events occurring in pembro and pbo arms respectively
• In patients with PD-L1 CPS ≥1, median EFS was 70.9 and 48.3 months for the pembro arm and pbo arm respectively
• No new safety signals were reported

Reference

Yungan Tao et al, Long-term results of the randomized, phase 3 KEYNOTE-412 trial of pembrolizumab (pembro) or placebo (pbo) plus concurrent chemoradiotherapy (CRT) for unresected, locally advanced head and neck squamous cell carcinoma (LA HNSCC). JCO 43, 6013, (2025). 

Docetaxel with Androgen Deprivation Therapy & Radiotherapy for the Treatment of High-Risk Localized Prostate Cancer: An ICECaP Individual Patient-Data Analysis

• Amongst 1690 patients treated in 4 RCTs (GETUG-12, DFCI 05-043, STAMPEDE, RTOG-0521), 9% had cN1 disease & 85% received long-term ADT+RT.
• Addition of docetaxel to RT+ADT showed no significant benefit in MFS (HR=0.89 [0.76-1.05], p=0.160) or OS (HR=0.88 [0.74-1.05], p=0.167), during a median follow-up of 10 yrs.
• A trend towards favorable impact of docetaxel was observed in patients with very high-risk disease (n=1054; MFS- HR: 0.86; 0.71-1.05, OS- HR: 0.85; 0.68-1.07) vs. those with high-risk disease (n=636; MFS- HR: 0.97; 0.74-1.27, OS- HR: 0.95; 0.71-1.28). The treatment effect did not differ significantly when stratified by risk group (p-interaction >0.1).
• Adding Docetaxel to RT+ADT may be beneficial for some of the HRLPC patients with very high-risk disease. Biomarker evaluation may help identify appropriate candidates for treatment intensification with docetaxel with RT+ADT.

  Reference

  Praful Ravi, et al. Docetaxel with androgen deprivation therapy (ADT) and radiotherapy (RT) for high-risk localized prostate cancer (HRLPC): An ICECaP individual patient-data (IPD) meta-analysis of randomized controlled trials (RCTs). JCO 43, 5013, (2025).

  NRG-BR003: Doxorubicin plus Cyclophosphamide Followed by Weekly Paclitaxel With or Without Carboplatin for Node-positive or High-risk Node-negative TNBC

• NRG-BR003 is a randomized phase III clinical trial comparing two chemotherapy regimens for node-positive or high-risk node-negative triple-negative breast cancer (TNBC). 
• The study investigates whether adding carboplatin to the standard treatment of doxorubicin plus cyclophosphamide followed by weekly paclitaxel improves outcomes.

Reference

Vicente Valero, et al. NRG-BR003: A randomized phase III trial comparing doxorubicin plus cyclophosphamide followed by weekly paclitaxel with or without carboplatin for node-positive or high-risk node-negative TNBC, JCO 43, LBA509, (2025).

ANZUP 1301: Mitomycin plus BCG as Adjuvant Intravesical Therapy for High-risk, Non–muscle-invasive Bladder Cancer (NMIBC)

• ANZUP 1301 trial investigates the efficacy and safety of combining mitomycin C and BCG as adjuvant intravesical therapy for high-risk, NMIBC.
• This randomized, phase 3 trial compares this experimental therapy to standard BCG alone. The study aims to determine if adding mitomycin to BCG can improve outcomes like recurrence and progression rates and assess the safety and quality of life impact of the combination treatment.

Reference

Dickon Hayne, et al, Mitomycin plus BCG as adjuvant intravesical therapy for high-risk, non–muscle-invasive bladder cancer: A randomized phase 3 trial (ANZUP 1301), JCO 43, LBA4504, (2025).